2011 proved to be another exciting year in the world of nephrology. 2010 was dominated with big clinical trials (SHARP, FHN, IDEAL), APOL1 gene variants, Propublica article on HD in the US, and medicare bundling. 2011 proved to be a big year in basic science. Below is a list of the top 10 nephrology-related stories as voted by the readers of RFN. This is by no means a complete list of all of the major news stories. Feel free to add to this list in the comment section below. I will summarize each of these studies/stories below in increasing order of votes as received in our year-end poll.
10. FDA approval of belatacept for use in kidney transplant induction therapy (15%)- In June the FDA approved the use of the selective T-cell costimulatory blocker (anti-CTLA-4) belatacept (Nulojix) for use in kidney transplantation as both induction and maintenance therapy. This was after the FDA reviewed both the BENEFIT and BENEFIT-EXT trials published in Transplantation in 2010. These trials examined the use of belatacept for induction therapy and as a replacement for calcineurin-inhibitors for maintenance therapy. The hope is that calcineurin-inhibitor based regimens can potentially be avoided in the future as these are associated with a decline in eGFR over time. These trials both showed an improvement in eGFR at 3 years as compared to cyclosporine based regimens with slightly more acute rejection. However, the major concern for belatacept is the increased risk of post transplant lymphoproliferative disease hence it cannot be given to EBV negative patients. Another issue with giving belatacept is that it is given IV at different schedules after transplant which could impart challenges. Nephron Power has a post about this story.
9. Success in treating myeloma kidney with bortezomib plus plasma exchange published in NEJM June (17%)- Using plasma exchange to treat myeloma cast nephropathy has been a controversial topic in the field of nephrology. The benefit in clearing free serum light chains with plasma exchange has become an increasingly popular approach. Investigators from the Mayo Clinic published a letter in NEJM in June of this year describing their experiences with using bortezomib in combination with plasma exchange in 14 patients with known or suspected myeloma cast nephropathy. 12 of the 14 patients (86%) treated with plasma exchange had a partial or complete response to the therapy. 6 of the 12 had a complete response with normalization of creatinine after 6 months. Only 2 were on HD after treatment. These results are encouraging, however a randomized clinical trial will be needed to confirm this.
8. Eculizumab for shiga associated HUS published in NEJM (21%)- The major outbreak of E. coli O104:H4 secondary to contaminated sprouts that occurred in Germany dominated the international news from May to June of this year. About 4000 people were infected and at least 46 died. Nephrologists in Germany were hit with an unprecedented number of patients with hemolytic uremic syndrome (HUS). This coincided with a report published in the NEJM in June of this year which demonstrated the complete resolution of Shiga-toxin-producing E. Coli- HUS in three children treated with eculizumab. This supported the concept that shiga toxin may activate complement directly and direct inhibition of terminal complement complex formation by treating patients with eculizumab. This lead to an ad hoc committee from the German Society of Nephrology to recommend all patients with renal or neurological and hematological symptoms treated with plasmapheresis. If no short-term improvement was seen then they recommended use of eculizumab. This has resulted in wider-spread use and now a clinical trial. This was definitely a positive outcome to a devastating condition. I'm sure we will see more of this drug in clinical use in the near future.
7. The DOSE study of bolus or drip diuretics in CHF (24%)- This was an interesting study of a common clinical conundrum (Do you give diuretics by bolus or continuous infusion in compensated CHF?) that was published in NEJM in March of this year and discussed on RFN by Finnian. This was a prospective double-blind randomized controlled trial consisting of 308 patients from 26 clinical sites testing 2 questions; how do high-dose (2.5 x home dose) vs. low-dose (home dose) diuretics and IV continuous vs. IV bolus loop diuretic strategies impact the 1. Efficacy (symptoms) or 2. Safety (change in creatinine) in patients with compensated heart failure? There were no significant differences between either of these endpoints in either high vs low and continuous vs. bolus diuretic administration. The high-dose group did have more improvement in dyspnea but a higher creatinine level was reached. Read Finnian's conclusion on his blog post.
6. sFLT-1 removal in preeclampsia published in Circulation in August (25%)- Another exciting development in nephrology is the publication of a pilot study aimed at removing the soluble fms-like tyrosine kinase 1 (sFlt-1) in women with preeclampsia which was published in the journal Circulation in August of this year. Nate originally discussed sFlt-1 role in preeclampia on RFN and it is interesting to see how far research has progressed since then. This study looked at the feasibility and safety of removing sFlt-1 using extracorporeal apheresis in 5 patients with preterm preeclampsia and elevated sFlt levels. The pilot study confirmed that this technique is possible and safe however, it was not able to address whether or not this approach will prolong pregnancy and improve both maternal and fetal outcomes. I'm sure a clinical trial will be forthcoming.
5. Bardoxolone for diabetic nephropathy published in NEJM July (27%)- The preliminary results from this trial were originally presented at ASN Kidney Week in 2010 which I discussed on RFN in December. The final results were published in NEJM in July and discussed by Gearoid on RFN and Joel on PBF. This was a phase 2, double-blind, randomized, placebo-controlled trial looking at 227 adults with CKD treated with various doses of the oral antioxidant inflammation modulator Bordoxolone or placebo for 52 weeks. This trial showed improvement of GFR at 24 and 52 weeks compared to placebo. However, much of this GFR improvement was lost at 56 weeks (4 weeks after stopping the drug). I think these results are provocative, however I am anxiously awaiting the results of the larger phase III clinical trial termed BEACON which is currently enrolling patients.
4. ACT trial of acetylcysteine in contrast nephropathy (30%)- This trial published in Circulation in August and discussed by Graham on RFN was another long debated clinical question in nephrology- (how do we prevent kidney injury when patients receive iodinated contrast agents?). This trial randomly assigned 2308 patients undergoing an intravascular angiographic procedure with 1 risk factor for contrast-induced acute kidney injury to either acetylcysteine (1200mg twice daily 1 day before and 1 day after the procedure) or placebo. Both groups received normal saline at a rate of 1ml/kg per hour 6-12 hr before and after. They did not find any difference between any of the primary or secondary outcomes comparing acetylcysteine vs. placebo. Read the conclusion and comments from Graham's RFN post. Overall, it appears that acetylcysteine's days for preventing contrast nephropathy are almost over.
3. Increased mortality in dialysis patients after 2-day break (41%)- This study published in NEJM in September examines how patients that receive thrice weekly dialysis fare over the 2-day interdialytic interval. This study retrospectively examined the death rates and cardiovascular related hospital admissions on the long 2-day interval vs. other days in 32,065 patients currently undertaking thrice weekly hemodialysis using the USRDS database. They found that indeed the 2-day interval was associated with increased all-cause mortality, infection-related mortality, cardiac arrest, MI, CHF, stroke and dysrhythmia as compared to other days. Evidence is continuing to point towards a more physiological dialysis regimen with daily dialysis. However, this study did not compare thrice weekly to nocturnal or daily dialysis.
2. The lupus nephritis maintenance phase of the ALMS trial published in NEJM November (44%)- Coming in at number 2 is the much awaited results of the maintenance arm of the Aspreva Lupus Management Study (ALMS) trial. The induction arm of the ALMS study compared Cyclophosphamide to Mycophenolate (MMF) and was published in JASN in 2009 and showed difference between the two therapies in inducing remission in lupus nephritis. The maintenance phase randomized patients that responded in the initial phase to either MMF or Azathiprine. 227 patients were randomized into each group. The patients randomized to MMF had better outcomes as compared to Azathioprine and puts MMF firmly on the map for both induction and now maintenance of lupus nephritis. However, there has been some conflicting data as was reported by the smaller MAINTAIN study that did not show a difference between these two regimens. This was a well conducted clinical trial that adds evidence to a difficult to treat condition. This is a welcome addition to patients with lupus and the nephrology and rheumatology communities.
1. suPAR as a cause of FSGS published in Nature Medicine in July (54%)- Coming in at number 1 in the 2011 nephrology poll at 54% of votes received was a basic science article published in Nature Medicine and discussed by Gearoid on RFN exploring the mechanism of focal segmental glomerulosclerosis (FSGS). This study showed that level of serum soluble suPAR urokinase receptor was present at higher concentrations in patients with FSGS. They then showed in 3 different animal models that elevated suPAR was capable of causing proteinuria and foot process effacement. We will see how these findings will be translated to human studies just as the discovery of the M-type phospholipase A2 receptor is for membranous nephropathy.
Again, quite a busy and exciting year in the world of nephrology in 2011. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.
Thanks for supporting RFN and happy holidays.
2 comments:
Regarding your top rated story on suPAR, I am afraid any serious student of immunology would have to vehemently disagree: this study is so highly flawed, it is surprising it was even published!
A review of the literature clearly shows that suPAR is elevated in various inflammatory conditions, it therefore seems so unlikely to be specifically responsible for recurrent FSGS. The most likely explanation is that suPAR is simply correlating with kidney disease, and therefore has no predictive value for FSGS per se. The study by Wei et al. confirms this actually, because the levels of suPAR do not correlate with the degree of proteinuria!
The mouse models used in this study, especially the suPAR injected mice, are fundamentally flawed experiments: Most importantly, the suPAR used for injection in mice is fused to a human Fc receptor, which means that a foreign antigen was injected into these mice! Surely, the immune response generated by this exposure to an allo-antigen would be enough to generate proteinuria, but this is not a model for FSGS, but rather, a model of serum sickness in a mouse exposed to a human antigen!
Similarly, there are many other experimental flaws in this study, including the fact that beta 3 integrin is specifically activated as a downstream target of suPAR.
The list of comments could go on, but the fundamental conclusion remains: this study is seriously flawed, and from an immunologist's standpoint, incredibly misguided. In time, the above mentioned flaws will most certainly be revealed, as I doubt anyone will be able to replicate these data, but I feel sorry for the many patients and their families, who may have been given false hope... What a shame...
thanks
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